The present invention relates to novel benzosultam oxazolidinones, specifically relates to N-substituted bicyclic benzosultam oxazolidinones; and their preparations. These compounds have potent antibacterial activities.
The oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. The benzosultam oxazolidinones of the present invention may also possess activities against gram-negative organisms such as Haemophilus influenza and Moraxella catarrhalis.
U.S. Pat. No. 5,164,510 discloses 5xe2x80x2-indolinyloxazolidin-2-ones which are useful as antibacterial agents.
U.S. Pat. Nos. 5,036,092; 5,036,093; 5,039,690; 5,032,605 and 4,965,268 disclose aminomethyl oxazolidinyl aza cycloalkylbenzene derivatives useful as antibacterial agents.
U.S. Pat. Nos. 5,792,765 and 5,684,023 disclose substituted oxazolidinones useful as antibacterial agents.
PCT International Publications WO 98/32438, WO 98/34929, WO 99/36069, WO 9911264, discloses sultam derivatives useful in the treatment of disease states mediated by the chemokine, interleukin-8.
The present invention provides a compound of formula I 
or a pharmaceutically acceptable salt thereof wherein:
R1 is H, NH2, NHC1-4 alkyl, C1-4 alkenyl, OC1-4 alkyl, SC1-4 alkyl, (CH2)ixe2x80x94C3-6 cycloalkyl, or C1-4 alkyl, optionally substituted with 1-3 F, 1-2 Cl or CN;
R2 is H, C1-12 alkyl optionally substituted with phenyl or CN, or C2-12 alkyl substituted with OH, SH, NH2, xe2x80x94OC1-6 alkyl, xe2x80x94NHC1-6 alkyl, xe2x80x94NHCOC1-6 alkyl, xe2x80x94NHSO2C1-6 alkyl, xe2x80x94S(O)iC1-6 alkyl, or one to three halo;
Y is O or S;
M is xe2x80x94(CH2)nxe2x80x94, wherein n is 1 or 2 and i is 0, 1, or 2.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
a method for treating microbial infections in humans or other warm-blooded animals by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof,
the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating microbial infections in humans or other warm-blooded animals, and
The invention also contains novel intermediates and processes that are useful for preparing compounds of formula I.
The following definitions are used, unless otherwise described.
The term alkyl, alkenyl, etc. refer to both straight and branched groups, but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-7 alkyl refers to alkyl of one to seven carbon atoms, inclusive.
Warm-blooded animals refer to farm animal, companion animal or other type of animal.
The term xe2x80x9chaloxe2x80x9d refers to fluoro, chloro, bromo, or iodo
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system.
Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d for hour or hours and xe2x80x9crtxe2x80x9d for room temperature).
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
A specific value for R1 is NH2, xe2x80x94OCH3, or C1-4 alkyl.
A specific value for R1 is methyl, ethyl, or isopropyl.
A specific value for R1 is methyl.
A specific value for R1 is ethyl.
A specific value for R2 is C1-6 alkyl.
A specific value for R2 is C1-6 alkyl substituted with CN.
A specific value for R2 is benzyl.
A specific value for R2 is C2-6 alkyl substituted with OH, SH, NH2, F, xe2x80x94OC1-6 alkyl, xe2x80x94NHC1-6 alkyl, xe2x80x94NHCOC1-6 alkyl, xe2x80x94NHSO2 C1-6 alkyl, xe2x80x94S(O)iC1-6 alkyl, or one to three halo.
A specific value for R2 is methyl or methyl substituted with CN.
A specific value for R2 is ethyl substituted with fluoro or methoxy.
A specific value for R2 is xe2x80x94CH2CH2F.
A specific value for Y is sulfur.
A specific value for Y is oxygen.
A specific value for n is 1.
These absolute configurations are called (S)-configuration according to the Cahn-Ingold-Prelog nomenclature system. It will be appreciated by those skilled in the art that compounds of the present invention may have additional chiral centers and be isolated in optically active or racemic form. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention. It is well known in the art how to prepare the optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity using the standard tests described herein, or using other similar tests which are well known in the art.
Examples of the present invention are:
(1) N-{[(5S)-3-(1-Methyl-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide, (PNU-252307)
(2) N-({(5S)-3-[1-(2-Fluoroethyl)-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide, (PNU-254380)
(3) N-({(5S)-3-[1-(2-Nitriloethyl)-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide, (PNU-274919)
(4) N-({(5S)-3-[1-(2-Methoxyethyl)-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide, and (PNU-276461)
(5) N-({(5S)-3-[1-(2-Fluoroethyl)-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethiomide. (PNU-254646)
The following describes the preparation of compounds of the present invention. All of the starting materials are prepared by procedures described herein or by procedures that would be well known to one of ordinary skill in organic chemistry.
As shown in CHART I, nitrobenzosultam 1, (can be obtained according to the methods described in J. Het. Chem. 1986, 23, 1645), is first converted to a sodium salt by treatment with a suitable base such as sodium bicarbonate. The nitrogen at the 1-position can then be alkylated by treatment with a variety of alkylating agents including alkyl halides and heating in a suitable solvent such as DMF. These compounds of general structure 2 can be reduced by catalytic hydrogenation in the presence of a suitable catalyst such as palladium on carbon in a suitable solvent such as ethyl acetate, THF, methanol or combinations thereof to afford 5-aminobenzosultams 3. When 3 are treated with magnesium triflate and N-[(2S)oxiranylmethyl] acetamide, prepared by the method of Schaus and Jacobsen (Tetrahedron Lett. 1996, 37, 7937), in a suitable solvent, preferably acetonitrile, the chiral alcohols 4 can be obtained. These compounds can be cyclized to the desired oxazolidinones 5 by reaction with a carbonyl equivalent such as carbonyl diimidazole or preferably N,Nxe2x80x2-disuccinimidyl carbonate with an appropriate base such as triethylamine in a mixed solvent system such as acetonitrile/DMF. Additionally, these oxazolidinone amides can be reacted with a sulfurating agent such as Lawesson""s Reagent in an appropriate solvent such as THF to obtain the corresponding thioamides 6. 
In CHART II, the compounds wherein n=2 can be prepared from the known intermediate 7 (Sianesi, E. et al. Chem. Ber. 1971, 104, 1880). Nitration of structure 7 provides structure 8. The remaining synthetic steps which lead to structure 9 are similar to the procedures outlined in CHART I. 
It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry.
The pharmaceutical compositions of this invention may be prepared by combining acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
Preferably, the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts of the active component, that is, the compounds of formula I according to this invention.
The quantity of active component, that is the compound of formula I according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
In therapeutic use for treating, or combating, bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof will be administered orally, topically, transdermally, and/or parenterally at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective. Generally, such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 500, preferably about 1.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
The compounds of formula I according to this invention are administered parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents. The compounds according to formula I generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/ml to about 400 mg/ml of solution. The resulting liquid pharmaceutical composition will be administered so as to obtain the abovementioned antibacterially effective amount of dosage. The compounds of formula I according to this invention are advantageously administered orally in solid and liquid dosage forms.
In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, (x-ketoglutarate, maleate, fumarate, benzenesulfonate and a-glycerophosphate. Suitable inorganic salts may also be formed, including hydrobromide, hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.